Getting Started with Genetics

Part One

Lesson 1: What does a gene do? Welcome to the Genetic Lifehacks "Getting Started with Genetics" course. This is a concise four-day long course on how to use your genetic data to optimize your diet and health.

My goal is to explain genetics to you in a way that is easy to understand - with lots of practical examples.

Instead of being a formal course, this will be more like a conversation about genetics.

So what exactly does a gene do?

A friend asked me that question recently... a friend that I had talked to a lot about genetics. The question made me realize that a lot of people have a general, fuzzy idea about what a gene is, but they don't always understand the underlying science. For a lot of us, it has been many years since biology class in high school.

Simply put...

Genes are the instructions, or the code, for a protein.

We often think of protein as something we eat -- e.g you might eat a steak or some eggs to get some protein.

In biology, though, a protein just means a series of amino acids that are bound together.

In your body, proteins make up the structure of a cell, and they act as enzymes that cause a reaction to take place. Proteins can also act as signals to regulate other functions taking place in the cell.

A lot of the genes that we will talk about in this course will code for proteins that act as enzymes. These enzymes are going to cause a reaction to take place in the cell - acting as a catalyst to make the reaction occur.

Example time:

The MTHFR gene codes for the methylenetetrahydrofolate reductase enzyme that acts within the folate cycle. (Quick tip: If a word ends in '-ase' it is usually an enzyme).

Within the cell, the folate that you got from eating some green vegetables must go through a series of steps to be used by the body. That final chemical reaction step is 'catalyzed' or caused by the MTHFR enzyme.

A common genetic variant in the MTHFR gene causes the enzyme not to function as well as the typical variant.

Take a quick minute and check your genetic data to see whether you carry the MTHFR C677T variant.

Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

• G/G: typical * • A/G: enzyme function decreased by ~40% • A/A: enzyme function decreased by ~70%

If you carry the variant (A/G or A/A), your MTHFR enzyme doesn't work as well as the typical version of this gene.

This means the body won't produce quite as much of the active form of folate (methyl folate).

Digging a little deeper: Enzymes only work in specific temperatures and at the right pH. This little change in the DNA code for the MTHFR gene causes the enzyme to be more sensitive to temperature, and it breaks down more quickly at normal body temp.

You can read all about the effects of this MTHFR variant here.

Back to enzymes (proteins):

We have lots of different enzymes in the body. These enzymes help to break apart the food we eat, cause reactions to take place within the cells, and initiate the transcription of genes - to create more proteins.

Genetic variants - changes in proteins:

Small changes to the way a protein is put together can change the way a protein works. Other changes can cause the protein not to work at all, which is usually bad...

Genetic changes affecting enzymes can cause reactions in cells to take place more slowly than normal - or more quickly.

Changes to structural proteins can cause problems with the way that cells function. Or, some changes just cause something really minor - such as hair color differences.

Resilience:

One thing that fascinates me about genetics is the overarching resilience that it shows us. In the example above with the MTHFR gene, a lot of people have variants that decrease the enzyme function. But the body has backup routes and other ways of dealing with the decrease in folate.

This resilience is what Genetic Lifehacks is all about. If you have a variant that decreases a cellular function, you can figure out how to bypass that and optimize your health.

To recap:

Genes code for proteins.

Proteins do most of the work in a cell:

• act as enzymes to cause a reaction to take place • make up the structure of cells • transport molecules within cells and outside of cells • send signals to start or end a process We are resilient and just need to figure out what is best for each of us, individually.

Part Two

Lesson 2: What is a SNP? Welcome back to the Genetic Lifehacks "Getting Started with Genetics" course!

Explaining some terminology...

Half the battle with learning about genetics is understanding the terms. It can be a bit like learning a few words in a foreign language.

When you start learning about genetics, you will see "SNP" used a lot. (People usually say "snip" for this acronym.)

SNP stands for 'single nucleotide polymorphism'. This simply means that one nucleotide in a gene is different from what is typically found in that spot in the sequence.

Wait - what are nucleotides?

Nucleotide bases are the A, C, G, and T's found in your DNA results.

"A" stands for adenine, C for cytosine, G for guanine, and T for thymine - these are the nucleotide bases that make up DNA.

Your DNA is made up of more than 3 billion pairs of these nucleotide bases. (Not all of your DNA codes for genes... later lesson!)

What happens if a change occurs?

Within a gene, if the typical DNA strand calls for an A and you have a G, then this is a change in the DNA that may (or may not) affect the protein that it codes for.

This would be considered a 'single nucleotide' change.

If that change is fairly common, it is called a 'polymorphism'. Technically, polymorphism means a change found in 1% or more of the population.

Thus, SNP = single nucleotide polymorphism = a change in one A/C/G/T that is more common

What about mutations?

Mutation is another way of stating that a gene has changed. In research, scientists use the word mutation when the genetic change is found in less than 1% of the population.

Thus, mutations are somewhat rare changes while polymorphisms are more common changes.

Why do Genetic Lifehacks articles refer to everything as a genetic variant?

Variant is more of a catch-all term meaning there is a change. This change could be a SNP, a mutation, or that a bit of code is inserted or deleted into the gene.

Example time:

When you drink alcohol, your body metabolizes it (breaks it down) using a two-step process.

Alcohol is first metabolized into acetaldehyde, and then the acetaldehyde is turned into acetate.

The ALDH1 gene codes for an enzyme called aldehyde dehydrogenase. (Note that it ends in "-ase", so it's an enzyme).

Check your genetic data for rs671 (23andMe v4, v5; AncestryDNA):

• A/A: Alcohol flush reaction • A/G: Alcohol flush reaction • G/G: Typical acetaldehyde metabolism People who have a single nucleotide change at a certain spot on the ALDH1 gene have an A instead of a G at that location. This causes a change in the way the enzyme functions.

People with this SNP will notice a tendency to flush when they drink alcohol, especially if drinking a lot or quickly.

This SNP causes a change in the aldehyde dehydrogenase enzyme which slows down the conversion of acetaldehyde into acetate. Too much acetaldehyde makes you flush and feel bad. (Acetaldehyde is toxic!)

Research shows that people with this polymorphism are less likely to become alcoholics - probably because they feel bad when they drink too much.

To recap:

• SNP = single nucleotide polymorphism • Polymorphisms are changes occurring in more than 1% of the population • SNPs may - or may not - cause changes to the way the protein functions • Mutations are changes in a gene. This term is usually used for changes found in less than 1% of the population

-> Tomorrow's topic: What can I learn from my genes?

Genetics Trivia

Did you know that the coloring on a Siamese cat is temperature-dependent? A mutation in the gene that codes for tyrosinase causes a change in the melanin pigment in Siamese cats. The mutation causes the tyrosinase enzyme to be more temperature sensitive. Thus, on the cooler parts of the Siamese cat's body - e.g. tail, the paws, ears - the enzyme works more efficiently and produces more pigment. This causes the fur on the legs, tail, ears, and face to be darker, while the fur on the warmer parts of the body ends up with less melanin and lighter. (source)

Part Three

Part 3: What can I learn from my genes? 

Welcome back to the Genetic Lifehacks "Getting Started with Genetics" course.

Why should I care about my genes?

This is something that I hear a lot!

People often think that their genes 'are what they are' and that knowing more about them doesn't change anything.

The key here is to understand your genetic variants so you can personalize your diet and prioritize lifestyle choices.

There are so many nutrition gurus and doctors on TV and the web that seem so sure their solutions are right for you. You know what I'm talking about -- the guy on YouTube in the tight t-shirt telling you to eat more saturated fat or the other guy with a white coat on TV telling you to never eat saturated fat.

Hypothetical situation:

One guru drinking carrot juice is all you need to do. This will give you all the vitamin A you need, keeping you healthy, thin, and able to leap tall buildings.

You buy the juicer he's selling and drink gallons of carrot juice. A year later you notice that your skin is orange, your night vision isn't great, and you can't leap tall buildings.

What's going on? Time for another example.

Example time:

The BCMO1 gene is responsible for the enzyme that converts beta-carotene into the active form of vitamin A needed by your body. SNPs in this gene cause it to not function as well, possibly leaving you deficient in vitamin A if you are only eating carrots.

There are two SNPs to check here, and carrying genetic variants in both SNPs can decrease your conversion of beta-carotene by 69%.

Check your genetic data for rs7501331 (23andMe v.4 and v.5, AncestryDNA):

• C/C: typical • C/T: decreased beta-carotene conversion • T/T: decreased beta-carotene conversion Check your genetic data for rs12934922 (23andMe v.4 and v.5):

• A/A: typical • A/T: decreased beta-carotene conversion • T/T: decreased beta-carotene conversion How can you use this information?

If you carry variants in both SNPs and have problems with night vision, dry eyes, rough skin (signs of vitamin A deficiency), you may want to get your vitamin A levels checked - or add in retinol sources of vitamin A such as beef liver to your diet.

Genetic Lifehacks article for all the details ->

I like to break down using genetic data into a couple of different compartments:

• optimizing diet (do I need carrots or liver?) • preventing diseases (am I at risk for diabetes?) • finding the root cause for things that plague me Disease Prevention:

Let me give you a quick example of preventing diseases. One completely preventable genetic disease is hemochromatosis, which is caused when too much iron builds up in the body and damages the organs. Eventually, this can lead to liver failure, diabetes, pancreatitis, joint pain, and more.

Normally, the body tightly regulates iron absorption, but mutations in the HFE gene can cause you to absorb too much iron from foods.

For someone with an HFE mutation, giving blood is an easy way to reduce iron and keep it from damaging organs. Simply knowing that you have the genetic mutation can help to prevent all the complications from storing too much iron.

Example time:

You can check to see if you carry the genetic variant (HFE C282Y) that is the most common cause of hemochromatosis. (Other rare mutations can also cause hemochromatosis, so you can't rule it out completely based on this one variant.)

Check your genetic data for rs1800562 (23andMe v4, v5; AncestryDNA):

• A/A: most common cause of hereditary hemochromatosis, highest ferritin levels (two copies of C282Y) • A/G: increased ferritin levels, can cause hemochromatosis, more of a problem if also carrying rs1799945 – C/G or G/G (below) • G/G: typical

Read more about iron build up -->

To recap:

• Learning about your genetic variants can help you to optimize nutrition, such as dialing in your need for certain vitamins. • You can use your genetic data to find out which chronic conditions you're at risk for. • Genetics can help you to figure out the root cause of different chronic issues.

Part Four

Part 4: Understanding Your Genetic Raw Data File 

Welcome back to the Genetic Lifehacks "Getting Started with Genetics" course. In this final email, I'm going to dive into what exactly you're looking at in your genetic raw data.

Let's get into some of the details.

We've talked about genes coding for proteins. And that proteins can act as enzymes, signaling molecules, and structural pieces for the cell.

I've explained a few ways you can use your genetic data to optimize your diet or prevent chronic conditions.

Now it is time to get to the nitty gritty.

What you are actually looking at with the data from 23andMe or AncestryDNA?

First things first, everyone should download their genetic raw data file and store it safely. This is your data... you own it and you should use it. (Need help? Download directions for 23andMe or AncestryDNA).

When you download the genetic raw data file, it is a ZIP file. Double click to unzip it, and move the .txt file to a safe location on your hard drive.

If you open the file using a text editor, it will look like this:

The first thing you will probably notice is that the file has a lot of data in it -- about 650,000 rows.

While this may seem large, it is actually less than 1% of your genome.

What do the columns mean?

The rsid column gives a unique identifier to each genetic variant listed. The numbers that start with 'rs' are a unique id for each genetic variant. This rs id is used worldwide to identify that particular change in the genome. (The 'rs' stands for reference SNP.)

Sometimes in 23andMe data you will see a number that starts with an "i" instead of "rs". These are an internal numbering system just for 23andMe.

The chromosome column let's you know which chromosome the SNP is located on. (recap: 23 pairs of chromosomes, numbered 1-22 and then X and Y)

The position is where on the chromosome the SNP is located. Researchers start the numbering from one end of the chromosome and mark the positions all along to the other end.

Finally, you see the "genotype" column. This will show you which nucleotide bases you have on each chromosome. For the first line of this data, on chromosome 1 at position 734462, I inherited an A from Mom and an A from Dad.

If you are looking at AncestryDNA data, it will look very similar, but you'll notice that the genotype is divided up into two separate columns - allele 1 and allele2. Together these two letters make up your genotype.

Example time:

When you look through the 650,000 rows of rs ids and genotypes, you'll notice that mixed in amongst the A, C, G, and Ts there will sometimes be a "D" or an "I".

D stands for deletion. This means for that particular position on a chromosome, you are missing a nucleotide base (or multiple nucleotide bases).

I stands for insertion. Similarly, at some spots in the genome, people have extra nucleotide bases inserted.

It isn't just you that has the extras or is missing a chunk -- at that spot in the genome, everyone will see a DD or a DI or an II.

So what is a chromosome, anyway?

You'll notice that your genetic data is listed by chromosome number. A chromosome is just the packaged up DNA in the nucleus of the cell. While we often picture chromosomes as separate and neat (below), that image is only true for when the cell is getting ready to divide. At other times, the chromosomes are more loosely jumbled together in the nucleus.

Your genetic data will list chromosomes 1 - 22 (you have two copies, one from mom, one from dad) and either an XX (female) or an X and a Y (male). In AncestryDNA data, the X chromosome information is labeled as chromosome 23 and the Y chromosome info is labeled 24.

Mitochondrial DNA

You'll also find at the end of your genetic raw data file some SNPs from your mitochondrial DNA. Cells contain organelles called mitochondria, which produce ATP for energy. The mitochondria have their own unique DNA. Mitochondria are inherited almost entirely from mom, so the mitochondrial DNA is often used in genealogy for determining maternal ancestry.

Orientation:

Your DNA is a double stranded helix. This means that for each position on a chromosome, you have a nucleotide on one side that is bound to a nucleotide on the other side of the DNA strand.

Researchers define which side of the DNA they are looking at by direction - either called forward and reverse or plus and minus strand.

This needs a picture...

Why is orientation important?

Everything in your genetic raw data file is given in the forward or plus orientation.

But.. not every SNP is defined by researchers on the plus strand. Some research studies refer to SNPs on the minus strand.

When reading through research on SNPs defined on the minus strand, you may need to mentally convert between the strands to match with your genetic data.

Just remember that...

A (adenine) always binds to T (thymine). Likewise, G (guanine) always binds to C (cytosine).

A = T and C = G

For Genetic Lifehacks articles, everything is going to be given on the plus strand to match with your genetic data.

What's up with the different versions numbers?

One of the most frequent questions that I get from readers is 'why isn't rs __ in my genetic data'?

Your genetic data file from 23andMe or AncestryDNA is only covering a tiny part of your genome. Less than 1%.

Periodically, the companies change which SNPs that they include in their sequencing of your genetic data.

Here's a quick breakdown of versions:

23andMe v5: mid-2017 --> now

23andMe v4: late-2013 --> mid-2017

23andMe v3: late 2010 --> 2013

AncestryDNA v2 from 2016 --> now

AncestryDNA v1 is prior to early 2016

You'll notice that all Genetic Lifehacks articles will tell which version of data the rs id is found in...

Wrapping this up!

Thanks so much for joining in on the Genetic Lifehacks "Getting Started with Genetics" email course!

My hope is that the background information in this email course has helped you understand a little more about your genetic data and how you can use it to optimize your health.

If you enjoyed this course and are not yet a Genetic Lifehack's member, I would encourage you to check out the benefits of membership.